Description: Muc4 is a unique molecule composed of a mucin subunit ASGP-1 and a transmembrane subunit ASGP-2, derived from a single gene, originally isolated from a highly metastatic ascites rat mammary adenocarcinoma and implicated in breast cancer progression. Molecular analyses have indicated that Muc4 is bifunctional as well as heterodimeric, due to its anti-adhesive/anti-recognition effects and its modulation of signaling via the receptor tyrosine kinase ErbB2. The current proposal is based on two ideas that Muc4 overexpression can promote tumor progression in mammary tumors and that dysregulation of Muc4 in breast tumors leads to its overexpression. Three seminal observations support these ideas. 1) MMTV-Muc4 transgenic mice inappropriately expressing Muc4 in the mammary gland exhibit hyperplasia and a novel invasive phenotype, even though they do not exhibit tumor formation. 2) Muc4 blocks contact inhibition of the Erk mitogenic pathway in transfected MCF7 breast tumor cells. 3) TGFbeta regulates Muc4 through a proteosomal degradation mechanism in normal mammary epithelial cells, but not in mammary tumor cells. Based on these observations, three aims have been proposed for further studies on the involvement of Muc4 in mammary tumor progression. Aim 1 will use MMTV-Muc4 transgenic mice and Muc4 knockout mice to test the hypothesis that Muc4 can contribute to tumor progression. These studies will also investigate whether the Muc4-induced changes in mammary gland development result from anti-adhesion or ErbB2 ligand effects and whether Muc4 can block Herceptin-induced immune cell killing of ErbB2-overexpressing tumors. Aim 2 will use Muc4-transfected MCF7 breast tumor cells to explore new signaling scenarios by which Muc4 may alter tumor cell behaviors that contribute to mammary tumor progression, particularly the pathway which Muc4 blocks to abrogates contact inhibition. Aim 3 will address the novel mechanism by which Muc4 is regulated post-translationally by TGFbeta via proteosomal degradation of the Muc4 precursor. Of particular interest is the hypothesis that a TGFbeta block of the Muc4 precursor processing enzyme shunts the Muc4 precursor into the proteosomal pathway. Relevance: This research is directed toward understanding the role of the membrane mucin Muc4 in breast cancer. Providing evidence for MUC4 contributions to breast tumor progression is a prelude to developing methods for therapeutic targeting of this molecule.